KR20060086942A - Pharmaceutical composition comprising P2Ｘ7 receptor antagonist and nonsteroidal anti-inflammatory drug - Google Patents

Abstract

The invention provides a pharmaceutical composition, pharmaceutical product or kit comprising a first active ingredient which is a P2X7 receptor antagonist, and a second active ingredient which is a nonsteroidal anti-inflammatory drug, for use in the treatment of inflammatory disorders.

Description

A pharmaceutical composition comprising a P2X7 receptor antagonist and a nonsteroidal anti-inflammatory drug {A PHARMACEUTICAL COMPOSITION COMPRISING A P2X7 RECEPTOR ANTAGONIST AND A NONSTEROIDAL ANTI INFLAMMATORY DRUG}

The present invention relates to a combination of pharmaceutically active substances for use in the treatment of anti-inflammatory diseases / disorders, in particular rheumatoid arthritis.

Chronic inflammatory disorders such as rheumatoid arthritis are highly complex disorders with polygenic and involve complex inflammatory and immune mechanisms. Treatment of these disorders has largely been dependent on experience with the use of various therapeutic agents with little understanding of the mechanisms involved. Recent studies suggest that two inflammation modulators, cytokines IL-1 and TNFalpha (TNFα), may play an important role in the anti-inflammatory process of rheumatoid arthritis.

The development of new agents for use in the treatment of inflammatory diseases / disorders is desirable.

According to the present invention there is provided a pharmaceutical composition comprising a first active ingredient which is a P2X ₇ receptor antagonist and a second active ingredient which is a nonsteroidal anti-inflammatory drug (NSAID).

P2X ₇ receptors (formerly known as P2Z receptors) are ligands present in various cell types, mainly cell types known to be involved in the inflammation / immune process, in particular macrophages, mast cells and lymphocytes (T and B). Gated ion channel. Activation of the P2X ₇ receptor by extracellular nucleotides, in particular adenosine triphosphate, is known to induce the release of interleukin-1β (IL-1β), among others.

Antagonists of the P2X ₇ receptor is completely or compound, or other substance capable of partially inhibiting the activation of P2X ₇ receptor.

Methods for assaying P2X ₇ receptor antagonism are known in the art, for example WO 01/42194 discloses that P2X ₇ receptor is activated using a receptor agonist in the presence of ethidium bromide (fluorescent DNA probe). Fluorescence increase in intracellular DNA-bound ethidium bromide is observed. Thus, fluorescence increase can be used to quantify the effect of a compound or substance on the P2X ₇ receptor as a measure of P2X ₇ receptor activation.

In WO 01/42194, the assay takes a 96-well flat microtiter plate to prepare wells 200 μl, 10 ⁻ suspension of THP-1 cells (2.5 × 10 ⁶ cells / ml) containing 10 ⁻⁴ M ethidium bromide. Test solution comprising 25 μl of high potassium buffer containing ⁵ M benzoylbenzoyl adenine triphosphate (bbATP, a known P2X ₇ receptor agonist), and 25 μl of high potassium buffer solution comprising 3 × 10 ⁻⁵ M test compound This is done by filling with 250 μl. The plate is covered with a plastic sheet and incubated at 37 ° C. for 1 hour. The plate is then read at a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit width: Ex 15 nm, Em 20 nm. By way of comparison, bbATP (a P2X ₇ receptor agonist) and pyridoxal 5-phosphate (P2X ₇ receptor antagonist) are used separately in the test as controls. From the reads obtained, the pIC ₅₀ value is calculated for the test compound (this value is a negative (-) logarithm of the concentration of compound required to reduce the bbATP agonist activity by 50%). PIC ₅₀ values greater than 5.5 usually indicate an antagonist.

Examples of P2X ₇ receptor antagonists include the compounds described in WO 00/61569, WO 01/42194, WO 01/44170 and WO 03/041707, the entire contents of which are incorporated herein by reference.

More specifically, in a first aspect of the invention, the P2X ₇ receptor antagonist is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

Wherein m represents 1, 2 or 3;

Each R ^1a independently represents a hydrogen or a halogen atom;

A ^a represents C (O) NH or NHC (O);

Ar ^a to

기를 나타내며;

Group;

X ^a is a bond, an oxygen atom or CO, (CH ₂ ) _1-6 , CH =, (CH ₂ ) _1-6 O, O (CH ₂ ) _1-6 , O (CH ₂ ) _2-6 O, O (CH ₂ ) _2-3 O (CH ₂ ) _1-3 , CR '(OH), (CH ₂ ) _1-3 O (CH ₂ ) _1-3 , (CH ₂ ) _1-3 O (CH ₂ ) _2-3 O, NR ^5a , (CH ₂ ) _1-6 NR ^5a , NR ^5a (CH ₂ ) _1-6 , (CH ₂ ) _1-3 NR ^5a (CH ₂ ) _1-3 , O (CH ₂ ) _2-6 NR ^5a , O (CH ₂ ) _2-3 NR ^5a (CH ₂ ) _1-3 , (CH ₂ ) _1-3 NR ^5a (CH ₂ ) _2-3 O, NR ^5a (CH ₂ ) _{2- 6} O, NR ^5a (CH ₂ ) _2-3 0 (CH ₂ ) _1-3 , CONR ^5a , NR ^5a CO, S (O) _n , S (O) _n CH ₂ , CH ₂ S (O) _n , A SO ₂ NR ^5a or NR ^5a SO ₂ group;

n is 0, 1 or 2;

R 'represents a hydrogen atom or a C ₁ -C ₆ alkyl group;

One of R ^2a and R ^3a is halogen cyano, nitro, amino, hydroxyl, or (i) C ₁ -C ₆ alkyl optionally substituted with one or more C ₃ -C ₆ cycloalkyl, (ii) C ₃ -C ₈ cycloalkyl, (iii) C ₁ -C ₆ alkyloxy optionally substituted with one or more C ₃ -C ₆ cycloalkyl, and (iv) C ₃ -C ₈ cycloalkyloxy, each of which groups is Optionally substituted with one or more fluorine atoms, the other of R ^2a and R ^3a represents a hydrogen or halogen atom;

R ^4a represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally including an oxygen atom, wherein the heterocyclic ring system is a fluorine atom, hydroxyl, carbo One or more independently selected from cyclic, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, —NR ^6a R ^7a , — (CH ₂ ) _r NR ^6a R ^7a and -CONR ^6a R ^7a Optionally substituted with a substituent, or

R ^4a represents a 3- to 8-membered saturated carbocyclic ring system substituted with one or more substituents independently selected from -NR ^6a R ^7a ,-(CH ₂ ) _r NR ^6a R ^7a and -CONR ^6a R ^7a Wherein the ring system is optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C ₁ -C ₆ alkyl;

r is 1, 2, 3, 4, 5 or 6;

R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl group;

R ^6a and R ^7a each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl, a C ₂ -C ₆ hydroxyalkyl or a C ₃ -C ₈ cycloalkyl group, or

R ^6a and R ^7a together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring;

only,

(a) when A ^a represents C (O) NH and R ^4a represents a 3- to 8-membered saturated aliphatic heterocyclic ring system comprising one nitrogen atom, X ^a is not ^a bond,

(b) when A ^a represents C (O) NH and X ^a represents ^a (CH ₂ ) _1-6 or O (CH ₂ ) _1-6 group, R ^4a is unsubstituted imidazolyl, unsubstituted mor Not polyyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl groups,

(c) when A ^a represents NHC (O) and R ^4a represents a 3- to 8-membered saturated aliphatic heterocyclic ring system comprising one nitrogen atom, X ^a is not ^a bond;

(d) when A ^a represents NHC (O) and X ^a represents O (CH ₂ ) _1-6 , NH (CH ₂ ) _1-6 or SCH ₂ , then R ^4a is unsubstituted 1-piperidinyl Or not an unsubstituted 1-pyrrolidinyl group,

(e) When A ^a represents NHC (O) and X ^a represents O (CH ₂ ) _2-3 NH (CH ₂ ) ₂ , R ^4a is not an imidazolyl group.

Compounds of formula (I) are described in WO 00/61569.

In a second aspect of the invention, the P2X ₇ receptor antagonist is a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:

In which D ^b represents CH ₂ or CH ₂ CH ₂ ;

E ^b represents C (O) NH or NHC (O);

R ^1b and R ^2b each independently represent a hydrogen or halogen atom or an amino, nitro, C ₁ -C ₆ alkyl or trifluoromethyl group;

R ^3b represents a group of the formula

;

;

X ^b represents an oxygen or sulfur atom or an NH, SO or SO ₂ group;

Y ^b represents an oxygen or sulfur atom or an NR ^11b , SO or SO ₂ group;

Z ^b is —OH, —SH, —CO ₂ H, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, -NR ^6b R ^7b , -C (O) NR ^8b R ^9b , imidazolyl, 1-methylimidazolyl, -N (R ^10b ) C (O) -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcar Carbonyloxy, C ₁ -C ₆ alkoxycarbonyloxy, -OC (O) NR ^12b R ^13b , -OCH ₂ OC (O) R ^14b , -OCH ₂ OC (O) OR ^15b or -OC (O) OCH ₂ Group OR ^16b ;

R ^4b represents a C ₂ -C ₆ alkyl group;

R ^5b represents a C ₁ -C ₆ alkyl group;

R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^12b and R ^13b each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or more hydroxyl groups;

R ^11b is a hydrogen atom, or hydroxyl, and C ₁ -C ₆ alkoxy in being independently selected denotes a optionally substituted with one or more substituents C _l -C ₆ alkyl group;

R ^14b , R ^15b and R ^16b each independently represent a C ₁ -C ₆ alkyl group;

Provided that (i) when E ^b represents NHC (O), X ^b represents 0, S or NH and Y ^b represents O, then Z ^b represents —NR ^6b R ^7b , where R ^6b represents a hydrogen atom; R ^7b represents a hydrogen atom or a C ₁ -C ₆ alkyl group substituted with one or more hydroxyl groups, (ii) E ^b represents NHC (O) and X ^b represents 0, S or NH and Y ^b is When NH is represented and R ^5b represents CH ₂ CH ₂ , Z ^b is not —OH or imidazolyl.

Compounds of formula (II) are described in WO 01/42194.

In a third aspect of the invention, the P2X ₇ receptor antagonist is a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof:

In which D ^c represents CH ₂ or CH ₂ CH ₂ ;

E ^c represents C (O) NH or NHC (O);

R ^1c and R ^2c each independently represent hydrogen, halogen, amino, nitro, C ₁ -C ₆ alkyl or trifluoromethyl, but R ^1c and R ^2c cannot both represent hydrogen atoms at the same time;

R ^3c represents a group of the formula

;

;

R ^4c is C ₁ -C ₆ An alkyl group;

X ^c represents an oxygen or sulfur atom or an NR ^13c , SO or SO ₂ group;

R ^5c represents hydrogen or R ^5c represents C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl, each of which is halogen, hydroxyl, (di) -C ₁ -C ₆ -alkylamino,- Y ^c -R ^6c ,

, 및 질소, 산소 및 황 중에서 독립적으로 선택되는 1 내지 4개의 헤테로원자를 포함하는 5- 또는 6-원의 헤테로방향족 환 중에서 선택되는 하나 이 상의 치환체로 임의로 치환될 수 있고, 헤테로방향족 환은 할로겐, 히드록실 및 C₁-C₆ 알킬 중에서 선택되는 하나 이상의 치환체로 임의로 치환될 수 있으며;

And one or more substituents selected from 5- or 6-membered heteroaromatic rings comprising 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaromatic ring is halogen, Optionally substituted with one or more substituents selected from hydroxyl and C ₁ -C ₆ alkyl;

Y ^c represents an oxygen or sulfur atom or an NH, SO or SO ₂ group;

R ^6c represents a group —R ^7c Z ^c , where R ^7c represents a C ₂ -C ₆ alkyl group Z ^c represents —OH, —CO ₂ H, —NR ^8c R ^9c , —C (O) NR ^10c R ^11c or -N (R ^12c ) C (O) -C ₁ -C ₆ When Y ^c represents an oxygen or sulfur atom or an NH group, R ^6c is further hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, -C (O) NR ^14c R ^15c , -CH ₂ OC (O) R ^16c , -CH ₂ OC (O) OR ^17c or -C (O) OCH ₂ OR ^18c ;

R ^8c , R ^9c , R ^10c , R ^11c and R ^12c each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group;

R ^13c is hydrogen, C ₃ -C ₈ cycloalkyl, or C ₃ -C _8, or represents a cycloalkyl-methyl, R ^13c is hydroxyl and C ₁ -C ₆ alkoxy optionally substituted with one or more substituents selected from C ₁ -Represents a C ₆ alkyl group;

R ^14c , R ^15c , R ^16c , R ^17c and R ^18c each independently represent a C ₁ -C ₆ alkyl group;

Provided that when E ^c is C (O) NH and X ^c is O, NH or N (C ₁ -C ₆ alkyl), R ^5c is not a hydrogen atom or an unsubstituted C ₁ -C ₆ alkyl group.

Preferred compounds of formula IV are those compounds wherein R ^5c is unsubstituted or substituted with a C ₁ -C ₆ alkyl group and the preferred substituent is -Y ^c -R ^6c . When R ^5c is substituted with a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms, the number of heteroatoms in the ring does not exceed two.

Compounds of formula IV are described in WO 01/44170.

In a fourth aspect of the invention, the P2X ₇ receptor antagonist is a compound of Formula VI or a pharmaceutically acceptable salt or solvate thereof:

Wherein m represents 1, 2 or 3;

Each R ^1d independently represents a hydrogen or halogen atom;

A ^d represents C (O) NH or NHC (O);

Ar ^d represents a group of the formula VII, VIII or IX

;

;

R ^2d and R ^3d One is halogen, nitro, amino, hydroxyl, or (i) C ₁ -C ₆ alkyl optionally substituted with one or more halogen atoms, (ii) C ₃ -C ₈ cycloalkyl, (iii) optionally substituted with one or more halogen atoms C ₁ -C ₆ alkoxy, and (iv) C ₃ -C ₈ A group selected from cycloalkoxy and R ^2d and R ^3d The other one represents hydrogen or a halogen atom;

R ^4d represents a group of the formula

;

;

X ^d represents an oxygen or sulfur atom or a> NR ^8d group;

n represents 0 or 1;

R ^5d represents a C ₁ -C ₅ alkyl group which may be optionally substituted with one or more substituents selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy;

R ^6d and R ^7d are each independently a hydrogen atom, C ₁ -C ₆ alkyl (hydroxyl, halogen, C ₁ -C ₆ alkoxy and (di) -C ₁ -C ₄ alkylamino (optionally one or more hydroxyl groups) Optionally substituted with one or more substituents selected from :), or C ₃ -C ₈ cycloalkyl (optionally substituted with one or more substituents selected from hydroxyl, halogen, and C ₁ -C ₆ alkoxy);

R ^8d represents a hydrogen atom or a C ₁ -C ₅ alkyl group which may be optionally substituted with one or more substituents selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy;

only,

(a) when n is 0, then A ^d is NHC (O),

(b) when n is 1 and X ^d represents oxygen and A ^d is C (O) NH, then both R ^6d and R ^7d are not simultaneously hydrogen atoms or unsubstituted C ₁ -C ₆ alkyl, or R ^{If one of 6d} and R ^7d represents a hydrogen atom, R ^6d and R ^7d The other is not unsubstituted C ₁ -C ₆ alkyl;

(c) when n is 1 and X ^d is oxygen, sulfur or> NH and A ^d is NHC (O), then R ^6d and R ^7d are not both hydrogen atoms or unsubstituted C ₁ -C ₆ alkyl at the same time; R ^6d and R ^7d If one represents a hydrogen atom, the other of R ^6d and R ^7d is not unsubstituted C ₁ -C ₆ alkyl or —CH ₂ CH ₂ OH.

Formula VI compounds are described in WO 03/41707.

In another embodiment of the invention, the P2X ₇ receptor antagonist is a compound of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof:

Wherein m represents 1, 2 or 3;

A ^e represents C (O) NH or NHC (O);

Y ^e represents N or CH;

X ^e is a bond, CO, (CH ₂ ) _1-6 , O (CH ₂ ) _1-6 , (CH ₂ ) _1-6 NH (CH ₂ ) _1-6 , (CH ₂ ) _1-6 O (CH ₂ ) _1-6 , NH (CH ₂ ) _1-6 ;

Z ^e represents NR ^2e R ^3e ;

R ^1e represents halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, wherein the alkyl or cycloalkyl group may be optionally substituted with one or more fluorine atoms;

R ^2e and R ^3e each independently represent a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, wherein the alkyl or cycloalkyl group is one selected from hydroxyl, halogen or C ₁ -C ₆ alkoxy Optionally substituted with the above groups, or

R ^2e and R ^3e together with the nitrogen atom to which they are attached form a 3- to 9-membered saturated mono- or bicyclic heterocyclic ring comprising 1 or 2 nitrogen atoms and optionally comprising an oxygen atom, Heterocyclic rings may be optionally substituted with one or more groups selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy.

Compounds of formula (XI) may be prepared as described in the references cited herein above.

In a further aspect of the invention, the P2X ₇ receptor antagonist is as follows:

2-Chloro-5-[[2- (2-hydroxy-ethylamino) -ethylamino] -methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide ,

2-chloro-5- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide,

(R) -2-chloro-5- [3-[(2-hydroxy-1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Benzamide,

2-chloro-5-[[2-[(2-hydroxyethyl) amino] ethoxy] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-Chloro-5- [3- [3- (methylamino) -propoxy] propyl] -N- (tricyclo [3.3.1.1 ^{3, 7]} dec-l-ylmethyl) benzamide,

2-chloro-5- [3- (3-hydroxy-propylamino) -propoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-chloro-5- [2- (3-hydroxypropylamino) ethylamino] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-chloro-5- [2- (3-hydroxypropylsulfonyl) ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-chloro-5- [2- [2-[(2-hydroxyethyl) amino] ethoxy] ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl)- Benzamide,

2-chloro-5-[[2-[[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino] ethyl] amino] -N- (tricyclo [3.3.1.1 ^3,7 ] Deck-1-ylmethyl) -benzamide,

2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide,

2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide,

2-chloro-5- (piperidin-4-ylsulfinyl) -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

5-chloro-2- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.l ^{3 , 7} ] dec-1-ylmethyl) -4-pyridinecarbox amides,

2-chloro-5- [3-[[(1R) -2-hydroxy-1-methylethyl] amino] propyl] -N- ( ^tricycle [3.3.1.1 ^3,7 ] dec-1-ylmethyl) 3-pyridinecarboxamide,

5-chloro-2- [3- (ethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide,

5-chloro-2- [3-[(2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide,

5-chloro-2- [3-[[(2S) -2-hydroxypropyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridine Carboxamide,

N- [2-methyl-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylcarbonyl) phenyl] ^-tricyclo [3.3.1.1 ^3,7 ] decane-1 Acetamide, or

Pharmaceutically acceptable salts or solvates thereof.

Pharmaceutically acceptable salts include, if applicable, acid addition salts derived from pharmaceutically acceptable inorganic and organic acids, for example chloride, bromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate , Benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate, succinate, lactate, article Rutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salts; Salts derived from pharmaceutically acceptable inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc and bismuth salts. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include primary, secondary and tertiary amines, cyclic amines such as arginine, betaine, choline and the like. Examples of pharmaceutically acceptable solvates include hydrates.

Examples of P2X ₇ receptor antagonists that may be used in the present invention include:

2-Chloro-5-[[2- (2-hydroxy-ethylamino) -ethylamino] -methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide , Dihydrochloride,

2-chloro-5- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, hydrochloride,

(R) -2-chloro-5- [3-[(2-hydroxy-1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Benzamide, hydrochloride,

2-chloro-5-[[2-[(2-hydroxyethyl) amino] ethoxy] methyl] -N- (tricyclo [3.3 .1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, Acetate (1: 1) salts,

2-chloro-5- [3- [3- (methylamino) propoxy] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, hydrochloride,

2-Chloro-5- [3- (3-hydroxy-propylamino) -propoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, hydrochloride,

2-Chloro-5- [2- (3-hydroxypropylamino) ethylamino] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, acetate (1: 1 ) Salts,

2-chloro-5- [2- (3-hydroxypropylsulfonyl) ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

2-chloro-5- [2- [2-[(2-hydroxyethyl) amino] ethoxy] ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl)- Benzamide, hydrochloride,

2-chloro-5-[[2-[[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino] ethyl] amino] -N- (tricyclo [3.3.1.1 ^3,7 ] Deck-1-ylmethyl) -benzamide,

2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, dihydrochloride,

2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, hydrochloride,

2-Chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, hydrochloride ,

2-chloro-5- (piperidin-4-ylsulfinyl) -N-tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide,

5-chloro-2- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide,

2-chloro-5- [3-[[(1R) -2-hydroxy-1-methylethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) 3-pyridinecarboxamide,

5-chloro-2- [3- (ethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide, hydrochloride,

5-chloro-2- [3-[(2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.l ^3,7 ] dec-1-ylmethyl) -4-pyridinecarbox Amides, hydrochloride,

5-chloro-2- [3-[[(2S) -2-hydroxypropyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridine Carboxamide, dihydrochloride, and

N- [2-methyl-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylcarbonyl) phenyl] ^-tricyclo [3.3.1.1 ^3,7 ] decane-1 Acetamide, hydrochloride.

The active ingredient used in the present invention may exist in stereoisomeric forms. The present invention includes all geometric and optical isomers of the active ingredient and mixtures thereof including racemates. Tautomers and mixtures thereof also form one aspect of the present invention.

In the present invention, the second active ingredient is a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs are compounds or substances that can completely or partially inhibit the enzyme cyclooxygenase (COX). This enzyme has at least two isoforms, COX-1 and COX-2, COX-1 is constitutively expressed in the lining of the stomach and acts to protect it, COX-2 is an inducible and unique role in the inflammatory process Do it. Selective COX-2 inhibitors are also known as COXIB.

The NSAIDs of the present invention can inhibit both COX-1 and COX-2, but are preferably selective for COX-2.

Examples of NSAIDs that may be used are ibuprofen, naproxen, aspirin, celecoxib (available under the trade name "Celebrex"), diclofenac (available under the trade name "Voltaren"), etodolac (available under the trade name "Lodine"), phenopropene (Trade name "Nalfon"), Indomethacin (trade name "Indocin"), Ketoprofen (trade name "Oruvail"), Ketoralak (trade name "Toradol"), Oxaprozin (trade name " Daypro "), Nabumeton (trade name" Relafen "), Sulindac (trade name" Clinoril "), Tolmetin (trade name" Tolectin "), Rofecoxib (trade name" Vioxx ") , Valdecoxib, rumaricoxib, meloxycamp, etoricoxib and parecoxib.

In one embodiment of the invention, the second active ingredient is a selective inhibitor of COX-2. In the context of this embodiment, selective inhibitors of COX-2 are described in Water , TD et. al ., Proc. Natl . Acad . Sci . USA , 1999, 96, 7563-7568 ) is a compound that exhibits at least 2: 1 in vitro selectivity for COX-2: COX-1 as measured by whole blood assays. Preferably, the selective inhibitor of COX-2 has an in vitro selectivity to COX-2: COX-1 of at least 5: 1, more preferably at least 10: 1, even more preferably at least 30: 1, most Preferably at least 100: 1. Examples of selective inhibitors of COX-2 that may be used in accordance with this embodiment include celecoxib, rofecoxib, valdecoxib, rumaricoxib, etoricoxib and parecoxib.

In one embodiment of the invention, the second active ingredient is celecoxib, which is a selective inhibitor of COX-2. The chemical name for celecoxib is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide ( Pennitig , T. et. al , J. Med . Chem ., 1997, 40, 1347-1365 ). Celecoxib is marketed by Pfizer under the trade name "Celebrex".

In another embodiment of the invention, the second active ingredient is rofecoxib, which is a selective inhibitor of COX-2. The chemical name of rofecoxib is 4- [4 '-(methylsulfonyl) phenyl] -3-phenyl- (5H) -furanone ( Chan, CC et al J. Pharmacol . Exp . Ther ., 1999, 290, 551- 560) . Ropecoxib is marketed by Merck Sharp & Dohme under the trade name "Vioxx".

In another embodiment of the invention the second active ingredient is valdecoxib, which is a selective inhibitor of COX-2. The chemical name of valdecoxib is 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide ( Talley , JJ et al J. Med . Chem ., 2000, 43, 775-777 ). Valdecoxib is marketed by Pfizer under the trade name "Bextra".

It has been found that the selection of the active ingredient according to the invention is advantageous because its selection yields an advantageous anti-inflammatory effect and can thus be used to treat a variety of acute and chronic inflammatory diseases / disorders such as rheumatoid arthritis and osteoarthritis. Treatment of an inflammatory disorder may involve a reduction in swelling and / or pain relief associated with such a disease. In this regard, the products of the present invention have proved advantageous in reducing or alleviating the pain caused by inflammatory joint disorders in particular.

Pharmaceutical compositions of the present invention may be prepared by mixing a first active ingredient with a second active ingredient. Thus, in a further aspect of the invention, there is provided a method of preparing a pharmaceutical composition comprising mixing a first active ingredient that is a P2X ₇ receptor antagonist and a second active ingredient that is a nonsteroidal anti-inflammatory drug.

Alternatively, the first and second active ingredients may be administered simultaneously (different from administration in combination as described above), sequentially or separately to treat inflammatory diseases. Continuous means that the first and second active ingredients are administered one after the other in any order. If the active ingredient is separated and administered separately for less than 4 hours, preferably for less than 2 hours, and more preferably for less than 30 minutes, it still has the desired effect.

Accordingly, the present invention also provides a pharmaceutical product for use concurrently, continuously or separately in a treatment comprising a combination of a formulation of a first active ingredient that is a P2X ₇ receptor antagonist and a formulation of a second active ingredient that is a nonsteroidal anti-inflammatory drug. to provide. The second active ingredient is preferably a selective inhibitor of CO-2.

In another embodiment, the invention comprises a formulation of a first active ingredient that is a P2X ₇ receptor antagonist, a formulation of a second active ingredient that is a nonsteroidal anti-inflammatory drug, and instructions for simultaneous, continuous or separate administration to a patient in need thereof. To provide a kit. The second active ingredient is preferably a selective inhibitor of COX-2.

The first and second active ingredients are conveniently administered orally or parenterally using conventional systemic dosage forms such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions. These dosage forms are often one or more pharmaceutically acceptable, which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavors and colorants. Will contain the ingredients. Preferably, the first and second active ingredients are delivered orally.

For the therapeutic uses described above, the dosage administered will of course vary depending on the first and second active ingredients used, the mode of administration, the desired treatment and the indicated disease or disorder. Generally, however, when administered orally, the total combined daily dose of the first and second active ingredients is in the range of 10 to 2000 mg, in particular 10, 20, 30, 40, 50, 100, 150, 200 or 300 to Satisfactory results will be obtained when 1800, 1500, 1200, 1000, 800, 700, 600, 500 or 400 mg.

Pharmaceutical compositions, pharmaceutical products or kits according to the invention may be administered in divided doses 1 to 4 times daily, preferably once or twice daily.

In one embodiment of the invention, the daily dose of the first active ingredient in the pharmaceutical composition, product or kit is 5 to 1000 mg, 5 to 800 mg, 5 to 600 mg, 5 to 500 mg, 5 to 400 mg, 5 To 300 mg, 5 to 200 mg, 5 to 100 mg, 5 to 50 mg, 20 to 1000 mg, 20 to 800 mg, 20 to 600 mg, 20 to 500 mg, 20 to 400 mg, 20 to 300 mg, 20 To 200 mg, 20 to 100 mg, 20 to 50 mg, 50 to 1000 mg, 50 to 800 mg, 50 to 600 mg, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, 50 To 100 mg, 100 to 1000 mg, 100 to 800 mg, 100 to 600 mg, 100 to 500 mg, 100 to 400 mg, 100 to 300 mg, or 100 to 200 mg; The daily dose of the second active ingredient is 1 to 200 mg, 1 to 100 mg, 1 to 50 mg, 1 to 25 mg, 5 to 200 mg, 5 to 100 mg, 5 to 50 mg, 5 to 25 mg, 10 To 200 mg, 10 to 100 mg, 10 to 50 mg or 10 to 25 mg; The daily doses of the first and second active ingredients may be administered in divided doses 1 to 4 times a day, preferably once or twice a day, wherein the first and second active ingredients are mixed and simultaneously It can be administered continuously or separately. Dosage regimens of this embodiment may be conveniently employed when both the first and second active ingredients are delivered by oral administration. Second active ingredients that can be used according to this embodiment include celecoxib, rofecoxib and valdecoxib.

The invention also provides the use of the pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of inflammatory disorders, in particular rheumatoid arthritis or osteoarthritis.

The present invention also provides a method of treating inflammation comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention to a patient in need of treatment for an inflammatory disorder, in particular rheumatoid arthritis or osteoarthritis.

In addition, the present invention

(a) a first active ingredient that is a (therapeutically effective) dose of a P2X ₇ receptor antagonist and

(2) A method of treating an inflammatory disorder, comprising administering a (therapeutically effective) dose of a second active ingredient, a nonsteroidal anti-inflammatory drug, to a patient in need thereof, simultaneously, sequentially or separately. .

In the context of the present specification, the term “treatment” also includes “prophylaxis” unless otherwise indicated. The terms "therapeutic" and "therapeutically" should be understood as appropriate.

Prevention is predicted to relate in particular to the treatment of a person deemed to be at a prior history, or otherwise at increased risk for the disease or disorder in question. Persons at risk of developing certain diseases or disorders generally include those having a family history of the disease or disorder, or those who have been identified by genetic testing or screening to be particularly easy to develop the disease or disorder.

The invention also relates to triple combination therapy for the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, inflammatory bowel disease, COPD, asthma, allergic rhinitis or cancer or neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease or stroke. It is about.

For the treatment of rheumatoid arthritis, the pharmaceutical composition of the present invention is a "biological agent" such as an IL-1 receptor antagonist (such as Anakinra) and an IL-1 trap, IL-18 receptor, anti-IL-6 Ab, anti -CD20 Ab, anti-IL-15 Ab and CTLA4Ig.

Suitable formulations that can be used in combination with the pharmaceutical compositions of the invention include cyclooxygenase inhibiting nitric oxide donors (CINOD) and "disease modifiers" (DMARD), for example cyclosporin A, leflunomide; Ciclesonide; Hydroxychloroquine, d-penicillamine, auranopine, or parenteral or oral gold may also be used.

The invention also relates to leukotriene biosynthesis inhibitors, 5-lipooxygenase (5-LO) inhibitors or 5-lipooxygenase activating protein (FLAP) antagonists (zileuton; ABT-761; fenleutone; tepoxalline; abbott ( Abbott) -79175; Abbott-85761; N- (5-substituted) -thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenol hydrazone; methoxytetrahydropyran, for example Geneca (Zeneca) ZD-2138; compound SB-210661; pyridinyl-substituted 2n cyanonaphthalene compound, eg L-739,010; 2-cyanoquinoline compound, eg L-746,530; indole and quinoline compound, eg For example MK-591, MK-886, and BAY x 1005) and a pharmaceutical composition of the present invention.

The invention also relates to pentothiazin-3-ones such as L-651,392; Amidino compounds such as CGS-25019c; Benzoxalamines such as ontazolast; Benzenecarboximideamides, for example BIIL 284/260; And compounds such as zafirlukast, ablucast, montelukast, franlukast, berlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and A pharmaceutical composition of the present invention having a receptor antagonist for leukotriene LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ selected from the group consisting of BAY x 7195.

The present invention also relates to pharmaceutical compositions of the invention having PDE4 inhibitors, including inhibitors of isoform PDE4D.

The invention also relates to a pharmaceutical composition of the invention having an antihistamine H ₁ receptor antagonist including cetirizine, loratadine, desloratadine, fexofenadine, astemizol, azelastine and chlorpheniramine.

The present invention also relates to pharmaceutical compositions of the present invention having a gastroprotective H ₂ receptor antagonist or proton pump inhibitor (eg omeprazole).

The present invention also relates to propylhexerine, phenylephrine, phenylpropanolamine, pseudoephedrine, napazoline hydrochloride, oxymethazolin hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorpinephrine hydrochloride. It relates to a pharmaceutical composition having an α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictor sympathomimetic agent.

In addition, the present invention is ypratropium bromide; Tiotropium bromide; Oxytropium bromide; Pyrenzepine; And anticholinergic agents comprising terenzepine.

The present invention also provides theophylline and aminophylline; Sodium chromoglycate; Or to a pharmaceutical composition of the present invention having methylzantanin comprising a muscarinic receptor (M1, M2 and M3) antagonist.

The present invention also provides modulators of chemokine receptor function, such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the CC family); A pharmaceutical composition of the present invention having CXCR1, CXCR3, CXCR4 and CXCR5 (for CXC family) and CX ₃ CR1 (for CX ₃ -C family).

The invention also relates to pharmaceutical compositions of the invention having insulin-like growth factor type I (IGF-I) mimetics.

In addition, the present invention (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists; (c) interleukin converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors including VLA-4 antagonists; (f) cathepsin; (g) glucose-6 phosphate dehydrogenase inhibitors; (h) kinin-B ₁ -and B ₂ -receptor antagonists; (i) anti-gout agents such as colchicine; (j) xanthine oxidase inhibitors such as allopurinol; (k) urinary urinary excretion agents such as probevenid, sulfinpyrazone, and benzbromarone; (1) growth hormone secretagogues; (m) converting growth factor (TGFβ); (n) platelet-derived growth factor (PDGF); (o) fibroblast growth factor, such as basic fibroblast growth factor (bFGF); (p) granulocyte macrophage colony stimulating factor (GM-CSF); (q) capsaicin cream; (r) NKP-608C; SB-233412 (Talnetant); And tachykinin NK ₁ and NK ₃ receptor antagonists selected from the group consisting of D-4418; And (s) an elastase inhibitor selected from the group consisting of UT-77 and ZD-0892; A pharmaceutical composition of the invention having (t) induced nitric oxide synthase inhibitor (iNOS), or (u) chemoattractant receptor-homologous molecule (CRTH2 antagonist) expressed in TH2 cells.

The pharmaceutical compositions of the present invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents that can be used in combination include induced nitric oxide synthase inhibitors (iNOS inhibitors), and cyclooxygenase inhibiting nitric oxide donor (CINOD) analgesics (eg paracetamol and tramadol), cartilage sparing agents, eg For example diacerane, doxycillin and glucosamine, and hyaluronic acid such as hyalgan and mysticsk.

In addition, the pharmaceutical compositions of the present invention can be used in combination with existing therapeutic agents for the treatment of inflammatory bowel disease (ulcerative colitis and Crohn's disease). Suitable agents that can be used include 5-amino-salicylate, thiopurine, azathioprine and 6-mercaptorurin.

In addition, the pharmaceutical compositions of the present invention may contain anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, It can be used in combination with VegF inhibitors and cell antagonists including metabolic agents such as anti-neoplastic agents, in particular vinca alkaloids such as vinblastine and vincristine.

In addition, the pharmaceutical compositions of the present invention can be used in combination with antiviral agents such as nonracept, AZT, acyclovir and famciclovir, and disinfecting compounds such as valances.

In addition, the pharmaceutical compositions of the present invention may be used in combination with calcium channel blockers, lipid lowering agents such as fibrates, beta-blockers, Ace inhibitors, angiotensin-2 receptor antagonists and platelet aggregation inhibitors.

In addition, the pharmaceutical compositions of the present invention can be used in CNS preparations, such as antidepressants (eg, sertraline), anti-Parkinson's disease drugs (eg, deprenyl, L-dopa, levyan, mirapex, MAOB inhibitors) For example selengin and lasagulin, comP inhibitors such as tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and neuronal nitric oxide synthase), and anti- Alzheimer's drugs can be used in combination with, for example, donepezil, tacrine, propentophylline or metriponate.

In addition, the pharmaceutical compositions of the present invention may be combined with osteoporotic agents such as roloxifene, droroxifene, lasopoxifen or posomax and immunosuppressive agents such as FK-506, rapamycin, cyclosporine and azathiopura Can be used.

The invention will be better understood by reference to the following illustrative examples.

The following P2X ₇ antagonists were used in the examples:

1.N- [2- methyl -5- (9-oxa-3,7- Diazabicyclo [3.3.1] -3- Ilcarbonyl ) Phenyl ]- Trisa ECLO [3.3.1.1 ^3,7 ] Decane-1-acetamide, Hydrochloride

P2X ₇ antagonist 1. (N- [2-methyl-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylcarbonyl) phenyl] -tricyclo [3.3.1.1 ^{3 , 7} ] decane-1-acetamide, hydrochloride) was prepared as follows.

a) 3- (4- methyl -3- Nitrobenzoyl ) -7- ( Phenylmethyl ) -9-Oxa-3,7- Diazabicyclo [3.3.1] Nonan

Ice cooling of oxalyl chloride (9.6 ml) in dichloromethane (30 ml) of 4-methyl-3-nitro-benzoic acid (10.O g) in dichloromethane (320 ml) with DMF (0.1 ml) To the solution was added dropwise over 45 minutes. The reaction mixture was stirred at rt for 1 h and then concentrated in vacuo. Acid chloride was taken up in THF (320 ml) and ice-cooled, followed by N, N-diisopropylethylamine (38 ml), followed by 3- (phenylmethyl) -9-oxa-3,7-diazabicyclo [3.3.1. ] Nonane, dihydrochloride (16.0 g) (prepared as described in WO 01/028992) was added in portions. The reaction was stirred for 18 hours, then diluted with ethyl acetate (600 ml), washed with water (2 x 200 ml) and saturated sodium bicarbonate (aq) (3 x l50 ml) and dried (MgSO ₄ ), Filtration and concentration gave the subtitle compound (18.5 g).

m / z = 382

b) 3- (3-amino-4- Methylbenzoyl ) -7- ( Phenylmethyl ) -9-Oxa-3,7- Diazabicyclo [3.3.1] Nonan

Reduced iron powder (7.9 g) was added to a stirred solution of the product of step a) (18.0 g) and ammonium chloride (7.5 g) in ethanol / water (3: 1, 320 ml) at 70 ° C. over 15 minutes. . The reaction mixture was heated to reflux for 2 hours, filtered and concentrated in vacuo. The residue was taken up in ethyl acetate (400 ml) and washed with water (2 x l50 ml), then the organic phase was dried (MgSO ₄ ) and concentrated in vacuo to give the subtitle compound (14.5 g).

m / z = 352

c) N- [2- methyl -5-[[7- ( Phenylmethyl ) -9-Oxa-3,7- Diazabicyclo [3.3.1] -3-yl] carbonyl] Phenyl ]- Tricyclo [3.3.1.1 ^3,7 Deccan -One- Acetamide

Prepared by the method of step a) using 1-adamantaneacetic acid and the product of step b). Recrystallization gave an (ethyl acetate) subtitle compound.

m / z = 528

d) N- [2- methyl -5- (9-oxa-3,7- Diazabicyclo [3.3.1] -3- Ilcarbonyl ) Phenyl ]- Trisa ECLO [3.3.1.1 ^3,7 ] Decane-1-acetamide, Hydrochloride

4M HCl in 1,4-dioxane (8 ml) was added to a solution of the product of step c) (13.0 g) in ethyl acetate (300 ml). The resulting precipitate was separated by filtration, suspended in ethanol (300 ml) and then 5% palladium on carbon was added. The reaction mixture was stirred for 36 h under 3 atmospheres of hydrogen. Methanol was then added under a nitrogen atmosphere, the catalyst was filtered off and the filtrate was concentrated in vacuo. Recrystallization (isopropanol: methanol 25: 1, 800 ml) gave the title compound (9.1 g).

m / z = 438 (M + H) ⁺

δ _H (400 MHz, d ₆ -DMSO, Me ₄ Si, 90 ° C.) 9.06 (1H, s), 7.64 (1H, s), 7.25 (1H, m), 7.19 (1H, m), 4.15 (2H, s ), 3.96 (2H, d, J 14 Hz), 3.35-3.23 (6H, m), 2.26 (3H, s), 2.14 (2H, s), 1.96 (3H, br s), 1.69-1.62 (12H, m ).

Example  One

NSAID Of P2X ₇  Antagonist Combination of  Pharmacological analysis to determine effect (P2X) ₇  No agents added)

Human peripheral blood monocytes were prepared from the blood of healthy human volunteers collected in EDTA blood tubes. Monocytes were separated by serial gradient centrifugation and washed to generate pure cell populations. Lipopolysacharide (LPS) was then added to the cell suspension of tissue culture and it was incubated at 37 ° C. for 4-12 hours. Subsequently, NSAID and / or P2X ₇ antagonist or vehicle was added to the cells. After incubation, samples of cell supernatants were transferred to 96-well plates for continuous cytokine and mediator measurements. The formation of inflammatory mediators was measured for cytokines IL-1, IL-18, TNFα, and other mediators including PGE2, NO and substrate metalloproteinases in specific cell-specific supernatants by ELISA assays. The levels of mediators secreted in the presence of P2X ₇ receptor antagonist alone, or in the presence of NSAIDs alone, or in combination of P2X ₇ receptor antagonists and NSAIDs were measured. The effects of the antagonist / NSAID alone and in combination were then compared. Compared with the inhibitory activity obtained by P2X ₇ antagonist or NSAID alone, the statistically significant level of inhibitory activity against the mediator alone (IL-1 or TNFα) or multiple mediators by P2X ₇ antagonist / NSAID combinations is associated with disease treatment. There is an indicator of increased efficacy.

Example  2

NSAID Of P2X ₇  Antagonist Combination of  Pharmacological analysis to determine effect (P2X) ₇  Under the addition of an agent)

Human peripheral blood monocytes were prepared from the blood of healthy human volunteers collected in EDTA blood tubes. Monocytes were separated by serial gradient centrifugation and washed to generate pure cell populations. LPS was then added to the cell suspension of tissue culture, which was incubated at 37 ° C. for 4-12 hours. The test mixture was then added followed by the P2X ₇ receptor agonist BzATP. The test mixture may comprise a vehicle, a P2X ₇ receptor antagonist, or a combination of P2X ₇ receptor antagonist and NASID. After incubation, samples of cell supernatants were transferred to 96-well plates for continuous cytokine and mediator measurements. The formation of inflammatory mediators was measured for cytokines IL-1, IL-18, TNFα, and other mediators, including PGE2, NO and substrate metalloproteinases, in a cell supernatant by specific ELISA assays. Increased levels of mediators were measured in the presence of P2X ₇ receptor antagonist alone or in the presence of a combination of P2X ₇ receptor antagonist and NSAID. The effects of P2X ₇ antagonist alone and in combination with NSAIDs were then compared. Compared with the inhibitory activity obtained by P2X ₇ antagonist alone, the statistically significant level of inhibitory activity against single mediators (IL-1 or TNFα) or multiple mediators by P2X ₇ antagonist / NSAID combinations increased in disease treatment. Is an indicator of efficacy.

Example  3A

In Rat Streptococcus Cell Wall-Induced Arthritis COX -2 inhibitor Celecoxib Of P2X ₇  Antagonist Combination of Anti-inflammatory  activation evaluation ^One

Streptococcal cell wall (SCW) -induced arthritis was induced in the left ankle of female Lewis rats. Animals were sensitized by intraarticular injection of 5 μg (in 20 μL) Lee Laboratories (SCW) at the left ankle. Swelling of the ankles was evaluated 3 days after injection, and non-responsive animals (animals without clear ankle swelling) were excluded. Responsive animals were randomly divided into test groups.

Arthritis was induced 21 days after sensitization by intravenous (iv) injection of SCW (100 μg, 500 μL saline). Animals were monitored and assessed daily until termination after 6 days of induction. Rats grew in sawdust and provided food and water in ad libitum .

In this example, P2X ₇ antagonist 1 was administered orally at 30 mg / kg (4 mL / kg, bid). The compound was prepared and administered freshly every day in a suspension of 1% (w / v) methylcellulose in deionized water. Dosing started one day before arthritis induction and continued daily until termination six days after induction. Celecoxib (3 mg / kg) was administered orally in the same regimen as for P2X ₇ antagonist 1 and celecoxib was administered immediately after administration of P2X ₇ antagonist 1.

Ankle diameter was measured with vernier calipers daily from -1 day. Mechanical thresholds were evaluated using von Frey filaments at days -1, 1, 3 and 5. The filaments were applied to the ankle area of the foot pads of both feet with increasing weight. The first filament causing the atrophic response was considered to be a threshold.

The effect on the ankle swell and mechanical threshold was calculated on the area under the curve (AUC) as the sum of the differences from each -1 day value. The magnitude and direction of the interactions were calculated and data analysis was performed by ANOVA followed by a Dunnet test on AUC data (SAS version 8.01). The results are shown in Table 1:

% Reduction in AUC (compared to arthritis vehicle control) Ankle swell Von Frey threshold P2X ₇ Antagonist 1 28.5 ± 13.5 21.1 ± 10.9 Celecoxib 63.0 ± 3.9 ** 43.2 ± 15.9 * P2X ₇ antagonist 1 + celecoxib 59.4 ± 6.2 ** 64.2 ± 10.3 ** interaction test p = 1.00 *** * p <0.01, ** p <0.001 vs arthritis vehicle control ***: Interaction score indicating addition benefits for the formulation

From the above results, it can be seen that the combination of P2X ₇ antagonist 1 and celecoxib exhibits a positive interaction reducing the mechanical threshold.

In a further study, P2X ₇ antagonist 1 was administered at doses of 10 and 30 mg / kg in combination with 1, 3 and 10 mg / kg of celecoxib, wherein the two active ingredients were co-administered as a single formulation. It became. The experimental endpoint is as described above. The results from these studies demonstrate a positive interaction that will reduce the mechanical threshold as described above. In addition, analysis of blood samples from these studies demonstrated that the pharmacodynamic profile of the two drugs administered in combination is the same as the pharmacodynamic profile of the drugs administered separately. This indicates that the observed positive effect is not the result of changes in the pharmacodynamic profile of the drug but the result of pharmacological interactions.

The discovery that the combination of P2X ₇ antagonist 1 and celecoxib, which have little beneficial effect on ankle swelling, has a positive effect on von Frey threshold, suggests that this combination of drugs has a significant and unexpectedly positive effect on inflammatory joint pain. Indicates.

1.Carlson RP, Jacobsen PB; 'Comparison of adjuvant and streptococcal cell wall-induced arthritis in the rat' in Morgan DW, Marshall LA, editors; In Vivo Models of Inflammation.Basel: Birkhauser Verlag; 1999 Bar based experiment

Example  3B

In Rat Streptococcus Cell Wall-Induced Arthritis COX -2 inhibitor Lopecoxib Of P2X ₇  Antagonist Combination of Anti-inflammatory  activation evaluation ^One

The anti-inflammatory activity of rofecoxib, a COX-2 inhibitor in combination with a P2X ₇ antagonist, was assessed using the protocol described in Example 3A. P2X ₇ antagonist 1 is oral at 30 mg / kg (4 mL / kg, bid) as a suspension of 1% (w / v) methylcellulose in deionized water as a single formulation with rofecoxib (Merck Sharp & Dohme Limited) Administered. Dosing commenced one day before the induction of arthritis continued daily until termination six days after induction. The results are summarized in Table 2.

% Reduction in AUC (compared to arthritis vehicle control) Ankle swell Von Frey threshold P2X ₇ Antagonist 1 2.6 ± 11.6 26.5 11.4 Lopecoxib 50.6 ± 4.7 ** 29.8 ± 7.8 * P2X ₇ antagonist 1 + rofecoxib 56.1 ± 6.4 ** 69.5 ± 6.6 ** interaction test p = 0. 44 *** * p <0.05, ** p <0.0001 vs arthritis vehicle control ***: Interaction score indicating addition benefits for the formulation

From the above results, it can be seen that the combination of P2X ₇ antagonist 1 and rofecoxib exhibits a positive interaction reducing the mechanical threshold. The discovery that the combination of two drugs that have little beneficial effect on ankle swelling has a positive effect on the von Frey threshold indicates that this combination of drugs has significant and unexpected positive effects on inflammatory joint pain. In addition, analysis of blood samples from these studies demonstrated that the pharmacodynamic profile of the two drugs administered in combination was the same as the pharmacodynamic profile of the drugs administered separately. This indicates that the observed positive effect is not the result of changes in the pharmacodynamic profile of the drug but the result of pharmacological interactions.

Example  3C

In Rat Streptococcus Cell Wall-Induced Arthritis COX -2 inhibitor Valdecoxib Of P2X ₇  Antagonist Combination of Anti-inflammatory  activation evaluation ^One

Anti-inflammatory activity of valdecoxib, a COX-2 inhibitor in combination with a P2X ₇ antagonist, was assessed using the protocol described in Example 3A. P2X ₇ antagonist 1 was administered orally at 30 mg / kg (4 mL / kg, bid) as a suspension of 1% (w / v) methylcellulose in deionized water as a single formulation with valdecoxib (Pfizer). Dosing commenced one day before the induction of arthritis continued daily until termination six days after induction. The results are summarized in Table 3.

% Reduction in AUC (compared to arthritis vehicle control) Ankle swell Von Frey threshold P2X ₇ Antagonist 1 2.6 ± 11.6 26.5 ± 11.4 Valdecoxib 52.8 ± 3.1 ** 37.8 ± 8.6 * P2X ₇ Antagonist 1 + Valdecoxib 57.4 ± 6.8 ** 60.9 ± 6.0 ** interaction test p = 0.85 *** * p <0.01, ** p <0.0001 vs arthritis vehicle control ***: Interaction score indicating addition benefits for the formulation

From the above results, it can be seen that the combination of P2X ₇ antagonist 1 and valdecoxib exhibits a positive interaction that reduces the mechanical threshold. The discovery that the combination of two drugs that show little beneficial effect on ankle swelling has a positive effect on the von Frey threshold indicates that this combination of drugs has a significant and unexpected positive effect on inflammatory joint pain. In addition, analysis of blood samples from these studies demonstrated that the pharmacodynamic profile of the two drugs administered in combination was the same as the pharmacodynamic profile of the drugs administered separately. This indicates that the observed positive effect is not the result of changes in the pharmacodynamic profile of the drug but the result of pharmacological interactions.

Claims (20)

A pharmaceutical composition comprising a mixture of a first active ingredient that is a P2X ₇ receptor antagonist and a second active ingredient that is a nonsteroidal anti-inflammatory drug. The composition of claim 1, wherein the P2X ₇ receptor antagonist is an adamantyl derivative. The composition of claim 1 or 2, wherein the P2X ₇ receptor antagonist is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. <Formula I>

Wherein m represents 1, 2 or 3; Each R ^1a independently represents a hydrogen or a halogen atom; A ^a represents C (O) NH or NHC (O); Ar ^a to

Group; X ^a is a bond, an oxygen atom or CO, (CH ₂ ) _1-6 , CH =, (CH ₂ ) _1-6 O, O (CH ₂ ) _1-6 , O (CH ₂ ) _2-6 O, O (CH ₂ ) _2-3 O (CH ₂ ) _1-3 , CR '(OH), (CH ₂ ) _1-3 O (CH ₂ ) _1-3 , (CH ₂ ) _1-3 O (CH ₂ ) _2-3 O, NR ^5a , (CH ₂ ) _1-6 NR ^5a , NR ^5a (CH ₂ ) _1-6 , (CH ₂ ) _1-3 NR ^5a (CH ₂ ) _1-3 , O (CH ₂ ) _2-6 NR ^5a , O (CH ₂ ) _2-3 NR ^5a (CH ₂ ) _1-3 , (CH ₂ ) _1-3 NR ^5a (CH ₂ ) _2-3 O, NR ^5a (CH ₂ ) _{2- 6} O, NR ^5a (CH ₂ ) _2-3 0 (CH ₂ ) _1-3 , CONR ^5a , NR ^5a CO, S (O) _n , S (O) _n CH ₂ , CH ₂ S (O) _n , A SO ₂ NR ^5a or NR ^5a SO ₂ group; n is 0, 1 or 2; R 'represents a hydrogen atom or a C ₁ -C ₆ alkyl group; One of R ^2a and R ^3a is halogen, cyano, nitro, amino, hydroxyl, or (i) C ₁ -C ₆ alkyl optionally substituted with one or more C ₃ -C ₆ cycloalkyl, (ii) C _3- C ₈ cycloalkyl, (iii) C ₁ -C ₆ alkyloxy optionally substituted with one or more C ₃ -C ₆ cycloalkyl, and (iv) C ₃ -C ₈ cycloalkyloxy, each of these groups Is optionally substituted with one or more fluorine atoms, and the other of R ^2a and R ^3a represents a hydrogen or halogen atom; R ^4a represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally including an oxygen atom, wherein the heterocyclic ring system is a fluorine atom, hydroxyl, carbo One or more independently selected from cyclic, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -NR ^6a R ^7a ,-(CH ₂ ) _r NR ^6a R ^7a and -CONR ^6a R ^7a Optionally substituted with a substituent, or R ^4a represents a 3- to 8-membered saturated carbocyclic ring system substituted with one or more substituents independently selected from -NR ^6a R ^7a ,-(CH ₂ ) _r NR ^6a R ^7a and -CONR ^6a R ^7a Wherein the ring system is optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C ₁ -C ₆ alkyl; r is 1, 2, 3, 4, 5 or 6; R ^5a represents a hydrogen atom or a C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl group; R ^6a and R ^7a each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl, a C ₂ -C ₆ hydroxyalkyl or a C ₃ -C ₈ cycloalkyl group, or R ^6a and R ^7a together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring; only, (a) when A ^a represents C (O) NH and R ^4a represents a 3- to 8-membered saturated aliphatic heterocyclic ring system comprising one nitrogen atom, X ^a is not ^a bond, (b) when A ^a represents C (O) NH and X ^a represents ^a (CH ₂ ) _1-6 or O (CH ₂ ) _1-6 group, R ^4a is unsubstituted imidazolyl, unsubstituted mor Not polyyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl groups, (c) when A ^a represents NHC (O) and R ^4a represents a 3- to 8-membered saturated aliphatic heterocyclic ring system comprising one nitrogen atom, X ^a is not ^a bond; (d) when A ^a represents NHC (O) and X ^a represents O (CH ₂ ) _1-6 , NH (CH ₂ ) _1-6 or SCH ₂ , then R ^4a is unsubstituted 1-piperidinyl Or not an unsubstituted 1-pyrrolidinyl group, (e) When A ^a represents NHC (O) and X ^a represents O (CH ₂ ) _2-3 NH (CH ₂ ) ₂ , R ^4a is not an imidazolyl group. The composition of claim 1 or 2, wherein the P2X ₇ receptor antagonist is a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof. <Formula II>

In which D ^b represents CH ₂ or CH ₂ CH ₂ ; E ^b represents C (O) NH or NHC (O); R ^1b and R ^2b each independently represent a hydrogen or halogen atom or an amino, nitro, C ₁ -C ₆ alkyl or trifluoromethyl group; R ^3b represents a group of the formula <Formula III>

; X ^b represents an oxygen or sulfur atom or an NH, SO or SO ₂ group; Y ^b represents an oxygen or sulfur atom or an NR ^11b , SO or SO ₂ group; Z ^b is —OH, —SH, —CO ₂ H, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ -alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, -NR ^6b R ^7b , -C (O) NR ^8b R ^9b , imidazolyl, 1-methylimidazolyl, -N (R ^10b ) C (O) -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcar Carbonyloxy, C ₁ -C ₆ alkoxycarbonyloxy, -OC (O) NR ^12b R ^13b , -OCH ₂ OC (O) R ^14b , -OCH ₂ OC (O) OR ^15b or -OC (O) OCH ₂ Group OR ^16b ; R ^4b represents a C ₂ -C ₆ alkyl group; R ^5b represents a C ₁ -C ₆ alkyl group; R ^6b , R ^7b , R ^8b , R ^9b , R ^10b , R ^12b and R ^13b each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with one or more hydroxyl groups; R ^11b is a hydrogen atom, or hydroxyl, and C ₁ -C ₆ represents a C _l -C ₆ alkyl group optionally substituted with one or more substituents independently selected from alkoxy, R ^14b , R ^15b and R ^16b each independently represent a C ₁ -C ₆ alkyl group; Provided that (i) when E ^b represents NHC (O), X ^b represents 0, S or NH and Y ^b represents O, then Z ^b represents —NR ^6b R ^7b , where R ^6b represents a hydrogen atom; R ^7b represents a hydrogen atom or a C ₁ -C ₆ alkyl group substituted with one or more hydroxyl groups, (ii) E ^b represents NHC (O) and X ^b represents 0, S or NH and Y ^b When is NH and R ^5b is CH ₂ CH ₂ , then Z ^b is not —OH or imidazolyl. The composition of claim 1 or 2, wherein the P2X ₇ receptor antagonist is a compound of Formula IV: or a pharmaceutically acceptable salt or solvate thereof. <Formula IV>

In which D ^c represents CH ₂ or CH ₂ CH ₂ ; E ^c represents C (O) NH or NHC (O); R ^1c and R ^2c each independently represent hydrogen, halogen, amino, nitro, C ₁ -C ₆ alkyl or trifluoromethyl, but R ^1c and R ^2c cannot both represent hydrogen atoms at the same time; R ^3c represents a group of the formula <Formula V>

; R ^4c represents a C ₁ -C ₆ alkyl group; X ^c represents an oxygen or sulfur atom or an NR ^13c , SO or SO ₂ group; R ^5c represents hydrogen or R ^5c represents C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl, each of which is halogen, hydroxyl, (di) -C ₁ -C ₆ -alkylamino,- Y ^c -R ^6c ,

And optionally substituted with one or more substituents selected from 5- or 6-membered heteroaromatic rings comprising 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the heteroaromatic ring is halogen, hydrate Optionally substituted with one or more substituents selected from hydroxyl and C ₁ -C ₆ alkyl; Y ^c represents an oxygen or sulfur atom or an NH, SO or SO ₂ group; R ^6c represents a group —R ^7c Z ^c , where R ^7c represents a C ₂ -C ₆ alkyl group Z ^c represents —OH, —CO ₂ H, —NR ^8c R ^9c , —C (O) NR ^10c R ^11c or -N (R ^12c ) C (O) -C ₁ -C ₆ alkyl group, when Y ^c represents an oxygen or sulfur atom, or NH group, R ^6c is further hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, -C (O) NR ^14c R ^15c , -CH ₂ OC (O) R ^16c , -CH ₂ OC (O) OR ^17c or -C (O ) OCH ₂ OR ^18c ; R ^8c , R ^9c , R ^10c , R ^11c and R ^12c each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group; R ^13c is hydrogen, C ₃ -C ₈ cycloalkyl, or C ₃ -C _8, or represents a cycloalkyl-methyl, R ^13c is hydroxyl and C ₁ -C ₆ alkoxy optionally substituted with one or more substituents selected from C ₁ -Represents a C ₆ alkyl group; R ^14c , R ^15c , R ^16c , R ^17c and R ^18c each independently represent a C ₁ -C ₆ alkyl group; Provided that when E ^c is C (O) NH and X ^c is O, NH or N (C ₁ -C ₆ alkyl), R ^5c is not a hydrogen atom or an unsubstituted C ₁ -C ₆ alkyl group. The composition of claim 1 or 2, wherein the P2X ₇ receptor antagonist is a compound of Formula VI: or a pharmaceutically acceptable salt or solvate thereof. <Formula VI>

Wherein m represents 1, 2 or 3; Each R ^1d independently represents a hydrogen or halogen atom; A ^d represents C (O) NH or NHC (O); Ar ^d represents a group of the formula VII, VIII or IX <Formula VII>

<Formula VIII>

<Formula IX>

; R ^2d and R ^3d One is halogen, nitro, amino, hydroxyl, or (i) C ₁ -C ₆ alkyl optionally substituted with one or more halogen atoms, (ii) C ₃ -C ₈ cycloalkyl, (iii) optionally substituted with one or more halogen atoms C ₁ -C ₆ alkoxy, and (iv) C ₃ -C ₈ A group selected from cycloalkoxy and R ^2d and R ^3d The other one represents hydrogen or a halogen atom; R ^4d represents a group of the formula <Formula X>

; X ^d represents an oxygen or sulfur atom or a> NR ^8d group; n represents 0 or 1; R ^5d represents a C ₁ -C ₅ alkyl group which may be optionally substituted with one or more substituents selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy; R ^6d and R ^7d each independently represent a hydrogen atom, C ₁ -C ₆ alkyl (hydroxyl, halogen, C ₁ -C ₆ alkoxy and (di) -C ₁ -C ₄ alkylamino (optionally one or more hydroxyl groups) Optionally substituted with one or more substituents selected from :), or C ₃ -C ₈ cycloalkyl (optionally substituted with one or more substituents selected from hydroxyl, halogen, and C ₁ -C ₆ alkoxy); R ^8d represents a hydrogen atom or a C ₁ -C ₅ alkyl group which may be optionally substituted with one or more substituents selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy; only, (d) if n is 0, then A ^d is NHC (O), (e) when n is 1 and X ^d represents oxygen and A ^d is C (O) NH, then both R ^6d and R ^7d are not simultaneously hydrogen atoms or unsubstituted C ₁ -C ₆ alkyl, or R ^6d And when one of R ^7d represents a hydrogen atom, R ^6d and R ^7d The other is not unsubstituted C ₁ -C ₆ alkyl; (f) when n is 1 and X ^d is oxygen, sulfur or> NH and A ^d is NHC (O), then R ^6d and R ^7d are not both hydrogen atoms or unsubstituted C ₁ -C ₆ alkyl at the same time; R ^6d and R ^7d If one represents a hydrogen atom, the other of R ^6d and R ^7d is not unsubstituted C ₁ -C ₆ alkyl or —CH ₂ CH ₂ OH. The composition of claim 1 or 2, wherein the P2X ₇ receptor antagonist is a compound of Formula (XI) or a pharmaceutically acceptable salt or solvate thereof. <Formula XI>

Wherein m represents 1, 2 or 3; A ^e represents C (O) NH or NHC (O); Y ^e represents N or CH; X ^e is a bond, CO, (CH ₂ ) _1-6 , O (CH ₂ ) _1-6 , (CH ₂ ) _1-6 NH (CH ₂ ) _1-6 , (CH ₂ ) _1-6 O (CH ₂ ) _1-6 , NH (CH ₂ ) _1-6 ; Z ^e represents NR ^2e R ^3e ; R ^1e represents halogen, cyano, nitro, amino, hydroxyl, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, wherein the alkyl or cycloalkyl group may be optionally substituted with one or more fluorine atoms; R ^2e and R ^3e each independently represent a hydrogen atom, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, wherein the alkyl or cycloalkyl group is at least one selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy Optionally substituted with a group, or R ^2e and R ^3e together with the nitrogen atom to which they are attached form a 3- to 9-membered saturated mono- or bicyclic heterocyclic ring comprising 1 or 2 nitrogen atoms and optionally comprising an oxygen atom, Heterocyclic rings may be optionally substituted with one or more groups selected from hydroxyl, halogen and C ₁ -C ₆ alkoxy. The method of claim 1, wherein the P2X ₇ receptor antagonist is 2-Chloro-5-[[2- (2-hydroxy-ethylamino) -ethylamino] -methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide , 2-chloro-5- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, (R) -2-chloro-5- [3-[(2-hydroxy-1-methylethyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl ) -Benzamide, 2-chloro-5-[[2-[(2-hydroxyethyl) amino] ethoxy] methyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- [3- [3- (methylamino) propoxy] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- [3- (3-hydroxy-propylamino) -propoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- [2- (3-hydroxypropylamino) ethylamino] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- [2- (3-hydroxypropylsulfonyl) ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- [2- [2-[(2-hydroxyethyl) amino] ethoxy] ethoxy] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl)- Benzamide, 2-chloro-5-[[2-[[2- (1-methyl-1H-imidazol-4-yl) ethyl] amino] ethyl] amino] -N- (tricyclo [3.3.1.1 ^3,7 ] Deck-1-ylmethyl) -benzamide, 2-chloro-5-piperazin-1-ylmethyl-N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, 2-chloro-5- (4-piperidinyloxy) -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 2-chloro-5- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -N- (tricyclo [3.3.1.1] dec-1-ylmethyl) -benzamide, 2-chloro-5- (piperidin-4-ylsulfinyl) -N-tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -benzamide, 5-chloro-2- [3-[(3-hydroxypropyl) amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide, 2-chloro-5- [3-[[(1R) -2-hydroxy-1-methylethyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) 3-pyridinecarboxamide, 5-chloro-2- [3- (ethylamino) propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridinecarboxamide, 5-chloro-2- [3-[(2-hydroxyethyl) amino] propyl] -N- (tricyclo [3.3.1.l ^3,7 ] dec-1-ylmethyl) -4-pyridinecarbox amides, 5-chloro-2- [3-[[(2S) -2-hydroxypropyl] amino] propyl] -N- (tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) -4-pyridine Carboxamide, N- [2-Methyl-5- (9-oxa-3,7-diazabicyclo [3.3.1] non-3-ylcarbonyl) phenyl] ^-tricyclo [3.3.1.1 ^3,7 ] decane- 1-acetamide, or A composition which is a pharmaceutically acceptable salt or solvate thereof. 9. The composition of claim 1, wherein the second active ingredient is a selective inhibitor of COX-2. 10. 10. The composition of claim 9 wherein the second active ingredient is celecoxib. 10. The composition of claim 9 wherein the second active ingredient is rofecoxib. 10. The composition of claim 9, wherein the second active ingredient is valdecoxib. The composition according to any one of claims 1 to 12, formulated for oral administration. 14. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 13, comprising mixing a first active ingredient with a second active ingredient. Use of a composition according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of an inflammatory disorder. Use according to claim 15, wherein the inflammatory disorder is rheumatoid arthritis or osteoarthritis. A method of treating an inflammatory disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1. 18. The method of claim 17, wherein the inflammatory disorder is rheumatoid arthritis or osteoarthritis. A pharmaceutical product comprising a formulation of a first active ingredient which is a P2X ₇ receptor antagonist for simultaneous, continuous or separate use in therapy and a formulation of a second active ingredient which is a nonsteroidal anti-inflammatory drug. A formulation of a first active ingredient that is a P2X ₇ receptor antagonist A kit comprising a formulation of a second active ingredient that is a nonsteroidal anti-inflammatory drug, and instructions for simultaneous, continuous or separate administration of the formulation to a patient in need thereof.